A direct effect of aspirin, an inhibitor of prostaglandin synthesis, on coronary blood flow in the nonischemic heart is not apparent. However, aspirin might indirectly influence coronary blood flow by interacting with vasodilator drugs. We studied this potential interaction in 24 open-chest dogs. Dogs were anesthetized with pentobarbitol, the chest was opened and an electromagnetic flow probe placed around a coronary artery. Drugs were injected directly into the coronary artery via a 27g lymphangiography needle inserted distal to the flow probe. Prostacyclin, 50-500 Ng, i.c., produced dose-dependent increases in coronary blood flow. Following aspirin, 10 mg/kg, i.v., the prostacyclin response on coronary blood flow was enhanced. Both peak flow and volume response were increased. Nitroglycerin, 4-120 micrograms; nitroprusside, 5-50 micrograms; and adenosine, 100-1000 Ng, also produced dose-dependent increases in coronary blood flow. The presence of aspirin did not alter dose-response curves of any of these compounds. Seven dogs received intravenous prostacyclin, 30-300 Ng/kg/min. The dose-dependent decreases in systemic arterial pressure were exacerbated in the presence of aspirin. Thus, aspirin potentiates the vasodilator response to prostacyclin in the systemic as well as the coronary circulation. Endogenous prostaglandin production is not essential to vasodilator effects of either nitroglycerin or nitroprusside for hearts with normal coronary arteries. Future studies will determine effects of vasodilators before and after aspirin in hearts with graded levels of coronary occlusion.